DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/28/2025 has been entered.
Applicant’s amendments to the claims filed on March 28, 2025 have been received and entered. Claims 1-17, 19-23 have been canceled. The objection to claims 24-26 are withdrawn in view of amendments to the claims. Claims 18, 24-25 and 26 have been amended.
Claims 18, 24-26 and 27 are pending in the instant application.
Priority
This application is a continuation of US application no 17830011 filed on June 1, 2022 which is a continuation of US application no 17/590,613 filed on 02/01/2022, now USP 11365407, which is a continuation of 17/366,290 filed on 07/02/2021 now USP 11254930, which is a continuation of 16/800,444 filed on 02/25/2020 now USP 11091756, which is a continuation of 16/601,144 filed on 10/14/2019, which claims priority from US provisional 62/864,432 filed on 06/20/2019, US provisional 62/830,654 filed on 04/08/2019, US provisional of 62/746,497 filed on 10/16/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/28/2025. 04/03/2025 and 05/03/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 18, 24-26 and 27 are under consideration.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 18, 24-26 and 27 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 29-33 of copending Application No. 18/680,273 and Jaskula-Ranga et al (WO/2018/009534, EFD07/5/2016, IDS)
Although the claims at issue are not identical, they are not patentably distinct from each other because claims in both applications are directed to an isolated eukaryotic cell comprising a genome with a transgene, wherein the transgene comprises from 5' to 3' orientation: a first splice donor reverse complement, a first coding sequence reverse complement, a first promoter reverse complement, a second promoter, a second coding sequence, and a second splice donor, wherein the first coding sequence is operably linked to the first splice donor and first promoter, and the second coding sequence is operably linked to the second splice donor and second promoter. In the instant case, claims are directed an isolated genetically modified eukaryotic cell comprising a transgene integrated within an intron of an endogenous gene, wherein the transgene comprises from 5' to 3' orientation :a first splice acceptor, a first coding sequence, a first terminator, a second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement, wherein the first coding sequence is operably linked to the first splice acceptor and first terminator, and the second coding sequence is operably linked to the second splice acceptor and second terminator, wherein the first and second coding sequences differ in nucleic acid sequence but each encode the same amino acid sequence, wherein said amino sequences encoded by the first and second coding sequences encodes a reporter protein-- or a purification tag, wherein the transgene is equal to or less than 4.7 kb, and wherein the transgene is operably linked to the promoter of the endogenous gene. Dependent claim limits the isolated eukaryotic cell of claim 18, wherein said amino sequence encoded by the first and second coding sequences encodes a reporter protein subsequently limiting to GFP, RFP, lacZ, Cat or luciferase. Claim 26 limits the herein said amino sequence encoded by the first and second coding sequences encodes a purification tag subsequently limiting he purification tag is glutathione-S-transferase, poly(his), maltose binding protein,Strep-tag, Myc-tag, HA-tag, or chitin binding protein. In contrast, claims in ‘273 are directed to a eukaryotic cell comprising a genome with a transgene, wherein the transgene comprises from 5' to 3' orientation: a first splice donor reverse complement, a first coding sequence reverse complement, a first promoter reverse complement, a second promoter, a second coding sequence, and a second splice donor, wherein the first coding sequence is operably linked to the first splice donor and first promoter, and the second coding sequence is operably linked to the second splice donor and second promoter, wherein the first and second coding sequences differ in nucleic acid sequence but encode the same amino acids, wherein the transgene is flanked by intron sequence of an endogenous gene within said genome, and wherein the transgene is operably linked to the terminator of the endogenous gene, wherein the transgene is equal to or less than 4.7 kb and herein said endogenous gene is aberrant or pathogenic and the partial coding sequences encode a partial protein produced from a functional version of said endogenous gen selected from the group consisting of D1, TRPV4, CHRNA1, CHRND, CHRNE, CHRNB1, PRPS1, LRRK2, STIM1, FGFR3, MECP2, SNCA, ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, AR, FXN, DMPK, PABPN1, ATXN8, RHO, or C9orf72. The ‘273 application differs from claimed invention by not disclosing inserting first coding sequence and a second coding sequence encodes a reporter or purification tag within intron of an endogenous gene.
However, prior to instant invention, Jaskula-Ranga cure the deficiency by disclosing a method of making viral vector more specifically AAV vector, said method comprising incorporating a nucleic acid construct into a viral particle to produce viral vector or more specifically AAV vector (see page 65, lines 22-34), wherein the construct comprising two coding sequences, a bidirectional promoter and an endonuclease (Claims 1, 15, page 3 line 25-31, page 4, line 15-26, page 5 line. 7, page 27 lines 8-20, page 40 line. 32-pahe 41 line. 8, example 6). It is further disclosed that the construct may comprises at least one that includes 2 terminator sequences (see claim 55-56) and wherein the that the coding sequence epitope tags include histidine (His) tags, Myc tags, reporter protein including luciferase, green fluorescent protein (GFP) (see page 52, lines 27-page 53). It would have been prima facie obvious for a person of ordinary skill to combine the teachings of ‘prior art by substituting first and second coding sequence as disclosed in ‘273 with GFP/purification tag as disclosed in Jaskula-Ranga, before the effective filing date of the instant invention, to produce AAV8 vector containing transgene comprising two [splice acceptor ~ coding sequence ~ terminator] cassettes arranged in tail-to-tail orientation. Said design choice amounting to combining prior art elements according to known methods to yield predictable results.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
New-Claim Rejections - 35 USC § 103- necessitated by amendments
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 18, 24-26 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Jaskula-Ranga et al (WO/2018/009534, EFD07/5/2016, IDS) as evidenced by Ohmori et al (Scientific Reports, 2017, 7, 4159, 1-11, IDS), Carlo et al (US20200040362, dated 02/06/2020, EFD, 06/28/2018) and Harrington et al (US6740503) as evidenced by Ni et al (PNAS, 2012, 38, 15389-15394)/ Sheng et al (Canadian Journal of Microbiology, 2014, 445-454, IDS) / Jarvis (US 2020/0231974, 7/23/2020, IDS) .
Claim interpretation: Instant rejection is applied to the breadth of the claims that does not require any expression and/functionality of coding sequence.
With respect to claim 18, 24-27, Jaskula-Ranga teaches a method of a method of altering expression of one or more gene products in a cell, wherein the cell comprises a DNA molecule encoding the one or more gene product, wherein the cells is an eukaryotic or non-eukaryotic cell mammalian cells (see page 11, line 32-33 to page 12, lines 7-9), said method comprising incorporating a nucleic acid construct into a viral particle to produce viral vector or more specifically AAV vector (see page 65, lines 22-34), wherein the construct comprising two coding sequences, a bidirectional promoter and an endonuclease (Claims 1, 15, page 3 line 25-31, page 4, line 15-26, page 5 line. 7, page 27 lines 8-20, page 40 line. 32-pahe 41 line. 8, example 6). It is further disclosed that the construct may comprises at least one that includes 2 terminator sequences (see claim 55-56). With respect to claims 18, 24-27, Jaskula-Ranga teaches that the coding sequence epitope tags include histidine (His) tags, Myc tags, reporter protein including luciferase, green fluorescent protein (GFP) (see page 52, lines 27-page 53). The concept of inserting a transgene within an intron of an endogenous gene FIX was disclosed in prior art as evidenced by Ohmori who teaches a method of inserting a transgene within an intron of an endogenous gene FIX, wherein said method comprising incorporaties chimeric DNA sequence (human F9 splice acceptor site and codon-optimized mouse F9 cDNA (exon 2–8)) and SV40 polyA) inserted within intron 1 of F9 gene (see page 8, last para, fig. 3a).
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While Jaskula-Ranga teaches incorporating a construct comprising at least one coding sequences (encompass 2 coding sequence), a bidirectional promoter and an endonuclease may comprises at least one that includes 2 terminator sequence (Claims 1, 15, page 3 line 25-31, page 4 , line 15-26, page 5 line. 7, page 27 lines 8-20, page 40 line. 32-pahe 41 line. 8, example 6, claims 55-56) into a AAV viral particle to produce AAV vector but differ from claimed invention by not disclosing a transgene comprising two (specie acceptor-coding sequence-terminator) cassettes arranged in tail-to-tail orientation.
Before the effective filing date of instant application Carlo et al teach donor polynucleotide comprises a coding sequence, wherein the first strand comprises a first coding sequence, wherein the second strand comprises a second coding sequence, wherein the first nucleotide sequence that corrects the mutation in the gDNA comprises the first coding sequence, wherein the second nucleotide sequence that corrects the mutation in the gDNA comprises the second coding sequence, wherein the first coding sequence is located downstream of the first 3' splice site (3 end of intron), and wherein the second coding sequence is located downstream of the second 3' splice site (3 end of intron) (see para. 46). Carlo et al teach a bi-directional insertion into a DSB donor polynucleotides provided by the disclosure are linear dsDNA molecules comprising two free DNA termini. As such, insertion of the donor polynucleotides into a DSB by the NHEJ machinery of a cell may occur in one of two orientations; forward and reverse. Accordingly, in some aspects, the disclosure provides donor polynucleotides that are configured for bi-directional insertion into a DSB introduced into gDNA by a site-directed nuclease, wherein the donor polynucleotide corrects or induces a mutation in a genomic DNA (gDNA) molecule in a cell and provides one or more splicing signals to control processing of a precursor mRNA (pre-mRNA) transcribed from the gDNA when inserted into a DSB in either orientation (see para. 446). It Harrington provided guidance with respect to use of splice acceptor sequence at 5' end of exon and/or 3’ end of intron boundary that could be selected by a person of ordinary skill in the art. Harrington teaches that a splice site is useful as each transcriptional regulatory sequence is operably linked to a separate splice site, and the transcriptional regulatory sequence/splice pairs may be in inverse orientation relative to each other (i.e., the first transcriptional regulatory sequence may be integrated into the host cell genome in an orientation that is inverse relative to the orientation in which the second transcriptional regulatory sequence has integrated into the host cell genome). The two opposing transcriptional regulatory sequence/splice sites can be separated (see col. 4 lines 24-36, col. 46 lines 28-39, 56-63, col. 48 lines. 34-43, col. 51 lines 30-37, col. 60 line57-64, col. 61 lines 8-16, col. 61 lines. 34-36, Fig. 11). The combination of reference differs from claimed invention by not disclosing the concept of construct comprising a transgene comprising in 5' to 3' orientation a first splice acceptor, a first coding sequence, a first terminator, a second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement or use of two terminators to integrate coding sequence.
However, before the filing of instant application, the concept of intronic insertions of a construct in tail-to-tail configuration was known in prior art. For instance, Ni teaches intronic insertion of FT1 construct comprising a splice acceptor and fluorescent reporter linked to a polyA terminator (see fig. S1). The FT1 cassette teaches use of dual splice acceptor and bidirectional terminators to express gene of interest (see fig. 2A and table 1)
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This is further evidenced by Sheng who teaches a method of introducing and integrating a into cells and expressing the polypeptide (GFP) in cells, said method comprising a constructs comprising two coding sequences encoding green fluorescent protein (figure 2). Sheng et al teaches a first coding sequence, a first terminator sequence, a second terminator reverse complement a second coding sequence of GFP reverse complement that is located 3' of the first, is highly complementary to the first (figure 2 page 446, col. 2 to page 447, col. 1) (limitation of claims).
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The use two cassette arranged in tail-to-tail orientation would be obvious to one of ordinary skill in the art before the effective filing of instant application as evident from the teaching of Jarvis who. teaches Figure 22 which shows a plasmid that having two open reading frames (ORFs) encoding T-cell receptor (TCRs) expression cassettes with a bidirectional terminator between those expression cassettes.
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The α-TCR ORF and β-TCR ORF encode identical amino acid sequence elements, CDR3-J-C-part-C.
It would have been prima facie obvious for a person of ordinary skill to combine the teachings of prior art to modify the human cells comprising nucleic acid comprises a transgene as disclosed in as disclosed in Jaskula-Ranga by incorporating a bidirectional construct containing first coding sequence for GFP and first terminator and a second terminator reverse complement and a second coding sequence for second coding sequence (GFP) reverse complement that are positioned 20in opposite orientation or a construct with bi-directional terminator as suggested in Sheng, Jarvis and Carlo, before the effective filing date of the instant invention, to produce a genetically modified human cells comprising a vector containing transgene comprising two [splice acceptor ~ coding sequence ~ terminator] cassettes arranged in tail-to-tail orientation. Said modification amounting to combining prior art elements according to known methods to yield predictable results. The limitation of using splice acceptor sequence in the bidirectional construct with two coding sequence would be obvious to a person of ordinary skill such that it could be positioned within intron of an endogenous transgene in opposite orientation flanking coding sequences and terminators such that following integration into intron in forward and/or reverse orientation thereby enabling removal of one upstream sequence. One of ordinary skill in the art would be motivated to do so because this would allow the construct to integrate in both forward and reverse direction and correct more than one mutation at different locations across the target gene. Absent evidence of any unexpected or superior results of the inserted transgene in the isolated eukaryotic cell, one of skill in the art would have been expected to have a reasonable expectation of success particularly since prior art successfully reported incorporating transgene in tail-to-tail configuration within an intron of endogenous gene as in Jarvis/Sheng/Ni. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Maintained -Claim Rejections - 35 USC § 112- in modified form
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18, 24-26 and 27 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph in modified form, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 18 is drawn to claims are directed an isolated genetically modified eukaryotic cell comprising a transgene integrated within an intron of an endogenous gene, wherein the transgene comprises from 5' to 3' orientation :any first splice acceptor, a first coding sequence, any first terminator, any second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement, wherein the first coding sequence is operably linked to the first splice acceptor and first terminator, and the second coding sequence is operably linked to the second splice acceptor and second terminator, wherein the first and second coding sequences differ in nucleic acid sequence but each encode the same amino acid sequence, wherein said amino sequences encoded by the first and second coding sequences encodes a reporter protein-- or a purification tag, wherein the transgene is equal to or less than 4.7 kb, and wherein the transgene is operably linked to the promoter of the endogenous gene.
The amended claim 18 encompasses a genus of cell comprising a transgene comprising a genus of first splice acceptor, a first coding sequence, a genus of first terminator, any second terminator reverse complement, a second coding sequence reverse complement, and any species second splice acceptor reverse complement, wherein the first coding sequence is operably linked to the first splice acceptor and first terminator, and the second coding sequence is operably linked to the second splice acceptor and second terminator integrated within any intron of any endogenous gene. The scope of the claim encompasses insertion of transgene into an intron of known or yet to be identified endogenous gene.
The specification teaches a novel transgene construct having the following structure: in a 5’ to 3’ direction, [splice acceptor 1] - [partial coding sequence 1]-[terminator 1] and a second nucleic acid having the elements [splice acceptor 2] [partial coding sequence 2] - [terminator 2] can be placed in tail-to-tail orientation resulting in [splice acceptor 1] - [partial coding sequence 1] -[terminator 1] -terminator 2 RC] - [partial coding sequence 2 RC] - [splice acceptor 2 RC], where RC refers to reverse complement.(see page 16, lines, line 18-23). The specification discloses the presence of rare-cutting endonuclease target sites flank splice acceptor sites in the transgene (see fig. 1, 6 and 7).
However, the specification does not provide adequate guidance for making any
specific, desired "integration of a transgene
within any intron of any endogenous gene " as broadly encompassed by claim 18, other than ATXN3 gene or CACNA1A gene (claim 18).
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The guidance provided in the specification is limited to a transgene that can be integrated within an intron of the endogenous gene or at an intron-exon junction of the ATXN3 gene or CACNA1A gene. The transgene can comprise a first and second partial coding sequence encoding the peptide produced by exon 10 of a non-pathogenic ATXN3 gene and can be targeted to intron 9, or the intron 9 exon 10 junction, of a pathogenic ATXN3 gene. The transgene can comprise a first and second partial coding sequence encoding the peptide produced by exon 47 of a non-pathogenic CACNA1A gene and can be targeted to intron 46, or the intron 46exon 47 junctions, of a pathogenic CACNA1A gene (see page 9, line 13-21, fig. 4, 6 see above).
The specification does not teach and does not enable to integrate a transgene within any intron of any other endogenous gene as embraced by the breadth of the claims. Further, the claims require the first and second coding sequences differ in nucleic acid sequence but encode the same amino acid sequence, wherein said amino sequence encoded by the first and second coding sequences encoding a reporter protein, a purification tag.
The amended claim encompasses a transgene that is integrated within any intron of any endogenous gene at a CRISPR/Cas9 nuclease target site, wherein the intron has a CRISPR/Cas9 target site prior to transgene integration. The instant specification as discussed above in fig. 5 and 6 explicitly discloses that the endonuclease target sites flank splice acceptor sites in the transgene for the purpose of directing integration of the transgene construct into the target genomic locus. It is emphasized that specification discloses a transgene comprising targeting sites at the 5' and 3' ends of the construct in order to direct integration into the genome and the correct functioning of the transgenes. The claims encompass a genus of first and second terminator reverse complement. The guidance provided in the specification is limited to use of bGH polyA sequence as set forth in SEQ ID NO: 5 and SV40 polyA as set forth in SEQ IDN O: 4. The art teaches terminator sequence are important in gene expression as their strength and potential for read-through transcription need to be considered. Ren (Synthetic and Systems Biotechnology 10 (2025) 326–335) teaches terminator characteristics contributed to the upstream mRNA stability and changing the composition of bases downstream of the terminator impact the efficiency of the terminator (see page 327, col. 1, para. 1-2). Ren discloses that terminators with varied strength affect upstream mRNA stability (see page 329, col. 1, apra. 2). The art further teaches that transgene inserted within an intron of an endogenous gene could interfere with function of the endogenous gene by disrupting the RNA splicing. Sironen et al (PNAS, 2006, 103, 5006-5011) studied the sequence analysis of a candidate gene KPL2 that showed the presence of an inserted retrotransposon within an intron. The insertion affected the splicing of the KPL2 transcript in two ways; it either causes skipping of the upstream exon, or causes the inclusion of an intronic sequence as well as part of the insertion in the transcript. Both changes alter the reading frame leading to premature termination of translation (abstract). In view of foregoing, it is apparent that insertion of transgene can introduce new splicing patterns, leading to the production of different mRNA isoforms that might have altered functions. The specification fails to disclose integrating a transgene comprising a first coding sequence, genus of first terminator, any second terminator reverse complement, a second coding sequence reverse complement within any intron of any endogenous locus other than a transgene can also comprise a first and second partial coding sequence and bGH polyA sequence as set forth in SEQ ID NO: 5 and SV40 polyA as set forth in SEQ IDN O: 4 that can be targeted into intron 9, or the intron 9 exon 10 junction, of a pathogenic ATXN3 gene or into intron 46, or the intron 46exon 47 junctions, of a pathogenic CACNA1A gene (see page 9, line 13-21, fig. 4, 6 see above). The specification lacks written description for "an isolated eukaryotic cell" comprising a transgene comprising a first splice acceptor, a first coding sequence, a genus of first terminator, any second terminator reverse complement, a second coding sequence reverse complement, and a second splice acceptor reverse complement integrated within any intron of any endogenous gene as broadly claimed for the reasons discussed above.
The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics. Inc., 48 USPQ2d 1641, 1646 (1998).
In the instant case, the claimed embodiments of eukaryotic cell comprising a transgene integrated within any intron or any endogenous gene, other than those exemplified for a transgene can also comprise a first and second partial coding sequence and bGH polyA sequence as set forth in SEQ ID NO: 5 and SV40 polyA as set forth in SEQ IDN O: 4 that can be targeted into intron 9, or the intron 9 exon 10 junction, of a pathogenic ATXN3 gene or into intron 46, or the intron 46exon 47 junctions, of a pathogenic CACNA1A gene encompassed within the genus of transgene combination sequences lack a written description. The specification fails to describe what DNA molecules fall into this genus of endogenous gene to be integrated within plurality of intron of a genus of endogenous gene. The skilled artisan cannot envision the detailed chemical structure of the encompassed by the transgene to be integrated into an endogenous gene, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
In view of the above considerations one of skill in the art would not recognize that applicant was in possession of the necessary common features or attributes possessed by member of the genus of transgene to be integrated within any intron of any endogenous gene, other than those exemplified for ATXN3 gene or CACNA1A.
Response to arguments
To the extent that Applicants’ arguments are pertinent to the new modified rejections, they are addressed as follows:
Applicant disagree with the rejection arguing that a person of ordinary skill in the art reading the applicant’s specification would have appreciated that the present claims are fully described. For example, applicant’s specification fully describes creating a genetically modified eukaryotic cell comprising a transgene within an intron of an endogenous gene, and fully describes that the first and second coding sequences can encode a reporter protein or purification tag. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it is noted that the issue pertains to a genus of isolated eukaryotic cells comprising a transgene integrated within any intron of any endogenous gene. The guidance provided in the specification is limited to a transgene that can be integrated within an intron of the endogenous gene or at an intron-exon junction of the ATXN3 gene or CACNA1A gene. The prior art teaches insertion of transgene within an intron may affect the splicing of the endogenous gene transcript either causing skipping of the upstream exon, or triggering the inclusion of an intronic sequence as well as part of the insertion in the transcript. It is emphasized that both changes alter the reading frame leading to premature termination of translation. The specification fails to provide adequate number of representative species by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the inserting a transgene within any intron of any endogenous or yet to be identified endogenous gene other than inserting the transgene comprising a first and second partial coding sequence and bGH polyA sequence as set forth in SEQ ID NO: 5 or SV40 polyA as set forth in SEQ IDN O: 4 that can be targeted into intron 9, or the intron 9 exon 10 junction, of a pathogenic ATXN3 gene or into intron 46, or the intron 46exon 47 junctions, of a pathogenic CACNA1A gene.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Finn (US 20200270617, EFD 10/18/2018) and INTELLIA THERAPEUTICS, ("Q3 2018 Earnings and Corporate Development", Powerpoint, 23 pages, presented 31 Oct 2018, IDS) teaches a nucleic acid construct is a bidirectional nucleic acid construct. In some embodiments, the construct comprises: i. a first segment comprising a coding sequence for a heterologous polypeptide; and ii. a second segment comprising a reverse complement of a coding sequence of the heterologous polypeptide. In some embodiments, the construct comprises a polyadenylation signal sequence. In some embodiments, the construct comprises a splice acceptor site. In some embodiments, the construct does not comprise a homology arm (see para. 12, Fig. 1-5). Finn is not applied as prior art as effective filing date of Finn is 2 days after the EFD of instant application.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ANOOP K SINGH/ Primary Examiner, Art Unit 1632
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